WO2020025512A1 - Catalytic ethynylation - Google Patents

Catalytic ethynylation Download PDF

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Publication number
WO2020025512A1
WO2020025512A1 PCT/EP2019/070295 EP2019070295W WO2020025512A1 WO 2020025512 A1 WO2020025512 A1 WO 2020025512A1 EP 2019070295 W EP2019070295 W EP 2019070295W WO 2020025512 A1 WO2020025512 A1 WO 2020025512A1
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Prior art keywords
formula
compound
carried out
present
process according
Prior art date
Application number
PCT/EP2019/070295
Other languages
French (fr)
Inventor
Fabrice Aquino
Werner Bonrath
Francesco Pace
Peter Ruckstuhl
Konrad Witzgall
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Dsm Ip Assets B.V.
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Publication date
Application filed by Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Priority to EP19742623.2A priority Critical patent/EP3830077A1/en
Priority to CN201980044961.3A priority patent/CN112399968A/en
Priority to US17/264,187 priority patent/US20210261488A1/en
Publication of WO2020025512A1 publication Critical patent/WO2020025512A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/02—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the alkali- or alkaline earth metals or beryllium
    • B01J23/04—Alkali metals

Definitions

  • the present invention relates to the catalytic ethynylation of a,b-unsaturated ketones for producing tertiary acetylenic alcohols.
  • ethynyated reaction products are important intermediates in organic synthesis.
  • ethynyl-b- ⁇ ohoI is an intermediate used in the preparation of vitamin A and b-carotene.
  • the present invention relates to a process (P) to produce compounds of formula (III)
  • R is hydrogen or an aliphatic, cyclo-aliphatic or aromatic hydrocarbon which can be unsubstituted or substituted with lower alkoxy or lower alkyl groups and
  • Ri is CH3 or CH2CH3, (a-alkynol),
  • the reaction is carried out with water or with a small amount of water, wherein the water is added at the end of the reaction. This is very advantageous for the further work up of the reaction product at the end of the process.
  • the process is very easy to handle.
  • the KOH is added to the reaction mixture in its pure form. No dilution step for KOH is needed. This step is not needed anymore.
  • R is an aliphatic, cyclo-aliphatic or aromatic hydrocarbon which is substituted with lower alkoxy or lower alkyl groups and
  • R1 is CH3.
  • the present invention also relates to a process (P1 ), which is process (P), wherein the compound of formula (I) and (III) R is an aliphatic or aromatic hydrocarbon which is substituted with lower alkoxy or lower alkyl groups and R 1 is CH 3 .
  • An especially preferred process according to the present invention relates to the pro- cess of production of the compound of formula (IN’)
  • the present invention also relates to a process (P2), which is process (P) or (P1 ), wherein the compound of formula (I) is the compound of formula (G)
  • the process according to the present invention is carried at low temperature. Usually the process is carried out at a temperature below +5°C. Preferably the process is carried out at a temperature of from -60°C to 5°C.
  • the present invention also relates to a process (P3), which is process (P), (P1 ) or (P2), wherein the process is carried out at a temperature below +5°C. Therefore, the present invention also relates to a process (P4), which is process (P), (P1 ), (P2) or (P3), wherein the process is carried out at a temperature of from -60°C to -5°C.
  • the reaction time of the process of the present invention is usually in the range of 0.5 to several hours, Usually the process is carried out during 0.5 - 12 hours.
  • the present invention also relates to a process (P5), which is process (P), (P1 ), (P2), (P3) or (P4), wherein the process is carried out during 0.5 - 12 hours.
  • the process of the present invention is carried out in the presence of ethyne (corn- pound of formula (II)).
  • Ethyne is also known as acetylene.
  • Ethyne is a colourless gas.
  • the reaction according to the present invention can be carried out at atmospheric condition by adding ethyne to the reaction mixture or it can be done at elevated pres- sure (usually 2 - 10 bar) in a pressure resistant vessel.
  • the present invention also relates to a process (P6), which is process (P), (P1 ), (P2), (P3), (P4) or (P5), wherein the process is carried out at atmospheric con- ditions. Therefore, the present invention also relates to a process (P7), which is process (P), (P1 ), (P2), (P3), (P4) or (P5), wherein the process is carried out at elevated pressure (usually 2 - 10 bar).
  • reaction according to the present invention is carried out with- out or with a small amount of water, wherein the water is added to the reaction mixture at the end of the reaction.
  • the present invention also relates to a process (P8), which is process (P), (P1 ), (P2), (P3), (P4), (P5), (P6) or (P7), wherein the process is carried without any water.
  • the present invention also relates to a process (P9), which is process (P), (P1 ), (P2), (P3), (P4), (P5), (P6) or (P7), wherein water is added to the reaction mix- ture at the end of the reaction process.
  • the present invention also relates to a process (P9’), which is process (P9), wherein less than 50 mol equivalent (in regard to mol of the compound of formula (I)) of water is added.
  • the present invention also relates to a process (P9”), which is process (P9), wherein between 1 - 50 mol equivalent (in regard to mol of the compound of formula (I)) of water is added.
  • the present invention also relates to a process (P9’”), which is process (P9), wherein between 2 - 20 mol equivalent (in regard to mol of the compound of formula (I)) of water is added.
  • the reaction product (compound of formula (III)) can be removed from the reaction mixture by commonly known processes. Usually it is done by extraction.
  • the compounds, which are produced by the process according to the present inven- tion are usually (and preferably) used in the manufacture of vitamin A or b-carotene.
  • the following examples illustrate the invention.
  • Example 1 66 mMol b-ionone were added to a mixture of 16 mMol KOH and 23 w% C2H2 in
  • the inorganic phase was separated from the organic phase, neutralized with AcOH and extracted with 150 ml n-hexane.
  • Example 2 The same reaction conditions as in Example 1 was chosen for Example 2. In addi- tion, 10 ml water were added after 1 hour.
  • the yield was 81 %.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to the catalytic ethynlation of αβ-unsaturated ketones for producing tertiary acetylenic alcohols.

Description

CATALYTIC ETHYNYLATION
The present invention relates to the catalytic ethynylation of a,b-unsaturated ketones for producing tertiary acetylenic alcohols.
The ethynyated reaction products, a-alkynols, are important intermediates in organic synthesis. For example, ethynyl-b-ίohoI is an intermediate used in the preparation of vitamin A and b-carotene.
The process for ethynylating of a,b-unsaturated ketones for producing tertiary acety- lenic alcohols is well known and described in many patent (i.e. in US3709946; US 3082260, US 3283014, US4147886 and US4320236).
In US4320236, the ethynylation is carried out in the presence of a monolithium acet- ylide-ammonia complex.
In US4147886, the ethynylation is carried out in the presence of diluted KOH.
Due to the importance of the ethynylated reaction products, there is always a need for an improved way to producing such products.
Surprisingly, it was found that the use of solid KOH in the reaction process allows to carry out the ethynylation process in an easy way.
Therefore, the present invention relates to a process (P) to produce compounds of formula (III)
Figure imgf000002_0001
wherein
R is hydrogen or an aliphatic, cyclo-aliphatic or aromatic hydrocarbon which can be unsubstituted or substituted with lower alkoxy or lower alkyl groups and
Ri is CH3 or CH2CH3, (a-alkynol),
wherein a compound of formula (I)
Figure imgf000003_0001
wherein the substituents have the same meanings as defined above is reacted with a compound of formula (II)
(P) in NH3 as a solvent and in the presence of KOH,
characterized in that KOH is added to reaction mixture in solid form.
Surprisingly the process is working without the addition of an aqueous solution of
The new process, which is characterized that the catalyst (KOH) is added in pure (= solid) form has some advantages in view of the prior art processes.
The reaction is carried out with water or with a small amount of water, wherein the water is added at the end of the reaction. This is very advantageous for the further work up of the reaction product at the end of the process.
Furthermore, the process is very easy to handle. The KOH is added to the reaction mixture in its pure form. No dilution step for KOH is needed. This step is not needed anymore.
The process according to the present invention is as disclosed above the following:
Figure imgf000003_0002
(i) (ii) KOH (solid)
(III) wherein R and R1 are as defined above. In a preferred embodiment of the present invention compounds of formula (III) are produced wherein
R is an aliphatic, cyclo-aliphatic or aromatic hydrocarbon which is substituted with lower alkoxy or lower alkyl groups and
R1 is CH3.
Therefore, the present invention also relates to a process (P1 ), which is process (P), wherein the compound of formula (I) and (III) R is an aliphatic or aromatic hydrocarbon which is substituted with lower alkoxy or lower alkyl groups and R 1 is CH3.
An especially preferred process according to the present invention relates to the pro- cess of production of the compound of formula (IN’)
Figure imgf000004_0001
by using the compound of formula (G)
Figure imgf000004_0002
as starting material.
Therefore, the present invention also relates to a process (P2), which is process (P) or (P1 ), wherein the compound of formula (I) is the compound of formula (G)
Figure imgf000004_0003
and the compound of formula (III) is the compound of formula (IN’)
Figure imgf000005_0001
The process according to the present invention is carried at low temperature. Usually the process is carried out at a temperature below +5°C. Preferably the process is carried out at a temperature of from -60°C to 5°C.
Therefore, the present invention also relates to a process (P3), which is process (P), (P1 ) or (P2), wherein the process is carried out at a temperature below +5°C. Therefore, the present invention also relates to a process (P4), which is process (P), (P1 ), (P2) or (P3), wherein the process is carried out at a temperature of from -60°C to -5°C.
The reaction time of the process of the present invention is usually in the range of 0.5 to several hours, Usually the process is carried out during 0.5 - 12 hours.
Therefore, the present invention also relates to a process (P5), which is process (P), (P1 ), (P2), (P3) or (P4), wherein the process is carried out during 0.5 - 12 hours. The process of the present invention is carried out in the presence of ethyne (corn- pound of formula (II)). Ethyne is also known as acetylene. Ethyne is a colourless gas. The reaction according to the present invention can be carried out at atmospheric condition by adding ethyne to the reaction mixture or it can be done at elevated pres- sure (usually 2 - 10 bar) in a pressure resistant vessel.
Therefore, the present invention also relates to a process (P6), which is process (P), (P1 ), (P2), (P3), (P4) or (P5), wherein the process is carried out at atmospheric con- ditions. Therefore, the present invention also relates to a process (P7), which is process (P), (P1 ), (P2), (P3), (P4) or (P5), wherein the process is carried out at elevated pressure (usually 2 - 10 bar).
As disclosed above the reaction according to the present invention is carried out with- out or with a small amount of water, wherein the water is added to the reaction mixture at the end of the reaction.
By the term“without any water” is meant that no water is added to the process inten- tionally. It might be that for example any used material of the process can comprise traces of water.
When water is used in the process according to the invention it is added at the end of the reaction (usually before the work up of the reaction mixture will be carried out).
Therefore, the present invention also relates to a process (P8), which is process (P), (P1 ), (P2), (P3), (P4), (P5), (P6) or (P7), wherein the process is carried without any water.
Therefore, the present invention also relates to a process (P9), which is process (P), (P1 ), (P2), (P3), (P4), (P5), (P6) or (P7), wherein water is added to the reaction mix- ture at the end of the reaction process.
When water is added it is added in a small amount. Usually not more than 50 mol equivalent (in regard to mol of the compound of formula (I)). Usually (and preferred) between 1 - 50 mol equivalent. More preferred 2 - 20 mol equivalent (in regard to mol of the compound of formula (I)).
Therefore, the present invention also relates to a process (P9’), which is process (P9), wherein less than 50 mol equivalent (in regard to mol of the compound of formula (I)) of water is added.
Therefore, the present invention also relates to a process (P9”), which is process (P9), wherein between 1 - 50 mol equivalent (in regard to mol of the compound of formula (I)) of water is added.
Therefore, the present invention also relates to a process (P9’”), which is process (P9), wherein between 2 - 20 mol equivalent (in regard to mol of the compound of formula (I)) of water is added. The reaction product (compound of formula (III)) can be removed from the reaction mixture by commonly known processes. Usually it is done by extraction.
The yields, conversions and selectivity of the process according to the present inven- tion are excellent.
The compounds, which are produced by the process according to the present inven- tion (compounds of formula (III)) are usually (and preferably) used in the manufacture of vitamin A or b-carotene. The following examples illustrate the invention.
All % are related to weight and the temperature is given in °C.
Examples
Example 1 66 mMol b-ionone were added to a mixture of 16 mMol KOH and 23 w% C2H2 in
NH3 and agitated for 1 h, at -10 °C at a pressure of 4.2 bar.
Afterwards 200 ml n-hexane were added slowly to the reaction mixture and the re- action mixture was degassed for about 2 h.
The inorganic phase was separated from the organic phase, neutralized with AcOH and extracted with 150 ml n-hexane.
The combined organic phases were washed with 150 ml water, dried on Na2S04, fil- tered and concentrated under vacuum.
The yield was 77%.
Example 2
The same reaction conditions as in Example 1 was chosen for Example 2. In addi- tion, 10 ml water were added after 1 hour.
The yield was 81 %.

Claims

1. A process for the production of compounds of formula (III)
Figure imgf000009_0001
wherein
R is hydrogen or an aliphatic, cyclo-aliphatic or aromatic hydrocarbon which can be unsubstituted or substituted with lower alkoxy or lower alkyl groups and
Ri is Chh or CH2CH3,
wherein a compound of formula (I)
Figure imgf000009_0002
wherein the substituents have the same meanings as defined for the compound of formula (III) is reacted with a compound of formula (II)
Figure imgf000009_0003
in NH3 as a solvent and in the presence of KOH,
characterized in that KOH is added to reaction mixture in solid form, and
wherein the process is carried without any addition of water.
2. Process according to claim 1 , wherein
R is an aliphatic or aromatic hydrocarbon which is substituted with lower alkoxy or lower alkyl groups and
R 1 is CH3.
3. Process according to any one of the preceding claims, wherein the compound of formula (I) is the compound of formula (G)
Figure imgf000010_0002
and the compound of formula (III) is the compound of formula (IN’)
Figure imgf000010_0001
4. Process according to any one of the preceding claims, wherein the process is carried out at a temperature below +5°C.
5. Process according to any one of the preceding claims, wherein the process is carried out at a temperature of from -60°C to 5°C.
6. Process according to any one of the preceding claims, wherein the process is carried out at atmospheric conditions.
7. Process according to any one of claims 1 - 5, wherein the process is carried out at elevated pressure.
8. Process according to any one of the preceding claims, wherein the process is carried without any addition of water.
PCT/EP2019/070295 2018-07-30 2019-07-29 Catalytic ethynylation WO2020025512A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP19742623.2A EP3830077A1 (en) 2018-07-30 2019-07-29 Catalytic ethynylation
CN201980044961.3A CN112399968A (en) 2018-07-30 2019-07-29 Catalytic ethynylation
US17/264,187 US20210261488A1 (en) 2018-07-30 2019-07-29 Catalytic ethynylation

Applications Claiming Priority (2)

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EP18186350 2018-07-30
EP18186350.7 2018-07-30

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3082260A (en) 1959-05-20 1963-03-19 Air Reduction Preparation of acetylenic alcohols
US3283014A (en) 1966-11-01 Acetylenic alcohols from ketones and acetylene using aqueous alkaline hy- droxide catalyst
US3709946A (en) 1970-07-31 1973-01-09 Air Prod & Chem Preparation of acetylenic alcohols
US4147886A (en) 1976-07-15 1979-04-03 Hoffmann-La Roche Inc. Process for the preparation of ethynyl-β-ionol
US4320236A (en) 1979-10-19 1982-03-16 Hoffmann-La Roche Inc. Ethynylation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3283014A (en) 1966-11-01 Acetylenic alcohols from ketones and acetylene using aqueous alkaline hy- droxide catalyst
US3082260A (en) 1959-05-20 1963-03-19 Air Reduction Preparation of acetylenic alcohols
US3709946A (en) 1970-07-31 1973-01-09 Air Prod & Chem Preparation of acetylenic alcohols
US4147886A (en) 1976-07-15 1979-04-03 Hoffmann-La Roche Inc. Process for the preparation of ethynyl-β-ionol
US4320236A (en) 1979-10-19 1982-03-16 Hoffmann-La Roche Inc. Ethynylation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TEDESCHI R J ET AL: "Base-Catalyzed reaction of Acetylene and Vinylacetylenes with Carbonyl Compounds in Liquid Ammonia under Pressure", JOURNAL OF ORGANIC CHEMISTRY,, vol. 28, 1 January 1963 (1963-01-01), pages 1740 - 1743, XP002264209, ISSN: 0022-3263, DOI: 10.1021/JO01042A002 *

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EP3830077A1 (en) 2021-06-09
US20210261488A1 (en) 2021-08-26

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